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Purpose: To develop an approach to the diagnosis and treatment of prostate cancer using one platform for fusion biopsy, followed by focal gland ablation utilizing permanent prostate brachytherapy with and without a rectal spacer. Material and methods: Prostate phantoms containing multiparametric magnetic resonance imaging (mpMRI) regions of interest (ROI) underwent fusion biopsy, followed by image co-registration of positive sites to a treatment planning brachytherapy program. A partial hemi-ablation and both posterior lobes using a Mick applicator and linked stranded seeds were simulated. Dummy sources were modeled as iodine-125 (125I) with a prescribed dose of at least 210 Gy to gross tumor (GTV) and clinical target volume (CTV), as defined by mpMRI visible ROI and surrounding negative biopsy sites. Computer tomograms (CT) were performed post-implant prior to and after rectal spacer insertion. Different prostate and rectal constraints were compared with and without the spacer. Results: The intra-operative focal volumes of CTV ranged from 6.2 to 14.9 cc (mean, 11.3 cc), and the ratio of focal volume/whole prostate volume ranged between 0.19 and 0.42 (mean, 0.31). The intra- and post-operative mean focal D90 of GTV, CTV, and for the entire prostate gland was 265 Gy and 235 Gy, 214 Gy and 213 Gy, and 66.1 Gy and 57 Gy, respectively. On average, 13 mm separation was achieved between the prostate and the rectum (range, 12-14 mm) on post-operative CT. The mean doses in Gy to 2 cc of the rectum (D2cc) without spacer vs. with spacer were 39.8 Gy vs. 32.6 Gy, respectively. Conclusions: Doses above 200 Gy and the implantation of seeds in clinically significant region for focal therapy in phantoms are feasible. All rectal dosimetric parameters improved for the spacer implants, as compared with the nonspacer implants. Further validation of this concept is warranted in clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Locally recurrent prostate cancer after previous radiation therapy remains challenging. One of the curative options for these patients is salvage brachytherapy. There are no reports available on the use of a biodegradable rectal balloon implantation (RBI) in combination with brachytherapy in patients with recurrent prostate cancer after previous radiotherapy. Case presentation: Here, we report on a patient with a local recurrence at five years after previous low-dose-rate brachytherapy with a prescribed dose of 145 Gray (Gy) for a low-risk prostate adenocarcinoma. The patient experienced grade 3 rectal toxicity, which was resolved at the time of local recurrence. He was treated with focal high-doserate (HDR) brachytherapy of 2 fr. x 13 Gy after RBI implantation. Four years post-salvage treatment, there was no evidence of biochemical recurrence according Phoenix definition, and no gastro-intestinal or genitourinary toxicity. Conclusions: This case describes the use of RBI implantation in combination with a focal salvage HDR in a patient with recurrent disease, with significant initial grade 3 rectal toxicity after previous irradiation. The use of a biodegradable RBI proved to be a promising solution for such a patient; however, this method needs to be further investigated. [ABSTRACT FROM AUTHOR]

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Stereotactic ablative body radiotherapy (SABR) is a novel non-invasive alternative for patients with primary renal cell cancer who do not undergo surgical resection. The FASTRACK II clinical trial investigated the efficacy of SABR for primary renal cell cancer in a phase 2 trial. This international, non-randomised, phase 2 study was conducted in seven centres in Australia and one centre in the Netherlands. Eligible patients aged 18 years or older had biopsy-confirmed diagnosis of primary renal cell cancer, with only a single lesion; were medically inoperable, were at high risk of complications from surgery, or declined surgery; and had an Eastern Cooperative Oncology Group performance status of 0–2. A multidisciplinary decision that active treatment was warranted was required. Key exclusion criteria were a pre-treatment estimated glomerular filtration rate of less than 30 mL/min per 1·73 m2, previous systemic therapies for renal cell cancer, previous high-dose radiotherapy to an overlapping region, tumours larger than 10 cm, and direct contact of the renal cell cancer with the bowel. Patients received either a single fraction SABR of 26 Gy for tumours 4 cm or less in maximum diameter, or 42 Gy in three fractions for tumours more than 4 cm to 10 cm in maximum diameter. The primary endpoint was local control, defined as no progression of the primary renal cell cancer, as evaluated by the investigator per Response Evaluation Criteria in Solid Tumours (version 1.1). Assuming a 1-year local control of 90%, the null hypothesis of 80% or less was considered not to be worthy of proceeding to a future randomised controlled trial. All patients who commenced trial treatment were included in the primary outcome analysis. This trial is registered with ClinicalTrials.gov , NCT02613819 , and has completed accrual. Between July 28, 2016, and Feb 27, 2020, 70 patients were enrolled and initiated treatment. Median age was 77 years (IQR 70–82). Before enrolment, 49 (70%) of 70 patients had documented serial growth on initial surveillance imaging. 49 (70%) of 70 patients were male and 21 (30%) were female. Median tumour size was 4·6 cm (IQR 3·7–5·5). All patients enrolled had T1–T2a and N0–N1 disease. 23 patients received single-fraction SABR of 26 Gy and 47 received 42 Gy in three fractions. Median follow-up was 43 months (IQR 38–60). Local control at 12 months from treatment commencement was 100% (p<0·0001). Seven (10%) patients had grade 3 treatment-related adverse events, with no grade 4 adverse events observed. Grade 3 treatment-related adverse events were nausea and vomiting (three [4%] patients), abdominal, flank, or tumour pain (four [6%]), colonic obstruction (two [3%]), and diarrhoea (one [1%]). No treatment-related or cancer-related deaths occurred. To our knowledge, this is the first multicentre prospective clinical trial of non-surgical definitive therapy in patients with primary renal cell cancer. In a cohort with predominantly T1b or larger disease, SABR was an effective treatment strategy with no observed local failures or cancer-related deaths. We observed an acceptable side-effect profile and renal function after SABR. These outcomes support the design of a future randomised trial of SABR versus surgery for primary renal cell cancer. Cancer Australia Priority-driven Collaborative Cancer Research Scheme. [ABSTRACT FROM AUTHOR]

Background and Objective: Owing to the greater use of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with biochemical recurrence (BCR) of prostate cancer (PCa) after robot-assisted radical prostatectomy (RARP), patient selection for local salvage radiation therapy (sRT) has changed. Our objective was to determine the short-term efficacy of sRT in patients with BCR after RARP, and to develop a novel nomogram predicting BCR-free survival after sRT in a nationwide contemporary cohort of patients who underwent PSMA PET/CT before sRT for BCR of PCa, without evidence of metastatic disease., Methods: All 302 eligible patients undergoing PCa sRT in four reference centers between September 2015 and August 2020 were included. We conducted multivariable logistic regression analysis using a backward elimination procedure to develop a nomogram for predicting biochemical progression of PCa, defined as prostate-specific antigen (PSA) ≥0.2 ng/ml above the post-sRT nadir within 1 yr after sRT., Key Findings and Limitations: Biochemical progression of disease within 1 yr after sRT was observed for 56/302 (19%) of the study patients. The final predictive model included PSA at sRT initiation, pathological grade group, surgical margin status, PSA doubling time, presence of local recurrence on PSMA PET/CT, and the presence of biochemical persistence (first PSA result ≥0.1 ng/ml) after RARP. The area under the receiver operating characteristic curve for this model was 0.72 (95% confidence interval 0.64-0.79). Using our nomogram, patients with a predicted risk of >20% had a 30.8% chance of developing biochemical progression within 1 yr after sRT., Conclusions: Our novel nomogram may facilitate better patient counseling regarding early oncological outcome after sRT. Patients with high risk of biochemical progression may be candidates for more extensive treatment., Patient Summary: We developed a new tool for predicting cancer control outcomes of radiotherapy for patients with recurrence of prostate cancer after surgical removal of their prostate. This tool may help in better counseling of these patients with recurrent cancer regarding their early expected outcome after radiotherapy., (© 2024 The Author(s).)

Purpose: The PERYTON trial is a multicenter randomized controlled trial that will investigate whether the treatment outcome of salvage external beam radiation therapy (sEBRT) will be improved with hypofractionated radiation therapy. A pretrial quality assurance (QA) program was undertaken to ensure protocol compliance within the PERYTON trial and to assess variation in sEBRT treatment protocols between the participating centers., Methods and Materials: Completion of the QA program was mandatory for each participating center (N = 8) to start patient inclusion. The pretrial QA program included (1) a questionnaire on the center-specific sEBRT protocol, (2) a delineation exercise of the clinical target volume (CTV) and organs at risk, and (3) a treatment planning exercise. All contours were analyzed using the pairwise dice similarity coefficient (DSC) and the 50th and 95th percentile Hausdorff distance (HD50 and HD95, respectively). The submitted treatment plans were reviewed for protocol compliance., Results: The results of the questionnaire showed that high-quality, state-of-the-art radiation therapy techniques were used in the participating centers and identified variations of the sEBRT protocols used concerning the position verification and preparation techniques. The submitted CTVs showed significant variation, with a range in volume of 29 cm 3 to 167 cm 3 , a mean pairwise DSC of 0.52, and a mean HD50 and HD95 of 2.3 mm and 24.4 mm, respectively. Only in 1 center the treatment plan required adaptation before meeting all constraints of the PERYTON protocol., Conclusions: The pretrial QA of the PERYTON trial demonstrated that high-quality, but variable, radiation techniques were used in the 8 participating centers. The treatment planning exercise confirmed that the dose constraints of the PERYTON protocol were feasible for all participating centers. The observed variation in CTV delineation led to agreement on a new (image-based) delineation guideline to be used by all participating centers within the PERYTON trial., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Purpose: Even though High Dose Rate (HDR) brachytherapy has good treatment outcomes in different treatment sites, treatment verification is far from widely implemented because of a lack of easily available solutions. Previously it has been shown that an imaging panel (IP) near the patient can be used to determine treatment parameters such as the dwell time and source positions in a single material pelvic phantom. In this study we will use a heterogeneous head phantom to test this IP approach, and simulate common treatment errors to assess the sensitivity and specificity of the error-detecting capabilities of the IP., Methods and Materials: A heterogeneous head-phantom consisting of soft tissue and bone equivalent materials was 3D-printed to simulate a base of tongue treatment. An High Dose Rate treatment plan with 3 different catheters was used to simulate a treatment delivery, using dwell times ranging from 0.3 s to 4 s and inter-dwell distances of 2 mm. The IP was used to measure dwell times, positions and detect simulated errors. Measured dwell times and positions were used to calculate the delivered dose., Results: Dwell times could be determined within 0.1 s. Source positions were measured with submillimeter accuracy in the plane of the IP, and average distance accuracy of 1.7 mm in three dimensions. All simulated treatment errors (catheter swap, catheter shift, afterloader errors) were detected. Dose calculations show slightly different distributions with the measured dwell positions and dwell times (gamma pass rate for 1 mm/1% of 96.5%)., Conclusions: Using an IP, it was possible to verify the treatment in a realistic heterogeneous phantom and detect certain treatment errors., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Germline and tumour genetic testing in prostate cancer (PCa) is becoming more broadly accepted, but testing indications and clinical consequences for carriers in each disease stage are not yet well defined., Objective: To determine the consensus of a Dutch multidisciplinary expert panel on the indication and application of germline and tumour genetic testing in PCa., Design Setting and Participants: The panel consisted of 39 specialists involved in PCa management. We used a modified Delphi method consisting of two voting rounds and a virtual consensus meeting., Outcome Measurements and Statistical Analysis: Consensus was reached if ≥75% of the panellists chose the same option. Appropriateness was assessed by the RAND/UCLA appropriateness method., Results and Limitations: Of the multiple-choice questions, 44% reached consensus. For men without PCa having a relevant family history (familial PCa/ BRCA -related hereditary cancer), follow-up by prostate-specific antigen was considered appropriate. For patients with low-risk localised PCa and a family history of PCa, active surveillance was considered appropriate, except in case of the patient being a BRCA2 germline pathogenic variant carrier. Germline and tumour genetic testing should not be done for nonmetastatic hormone-sensitive PCa in the absence of a relevant family history of cancer. Tumour genetic testing was deemed most appropriate for the identification of actionable variants, with uncertainty for germline testing. For tumour genetic testing in metastatic castration-resistant PCa, consensus was not reached for the timing and panel composition. The principal limitations are as follows: (1) a number of topics discussed lack scientific evidence, and therefore the recommendations are partly opinion based, and (2) there was a small number of experts per discipline., Conclusions: The outcomes of this Dutch consensus meeting may provide further guidance on genetic counselling and molecular testing related to PCa., Patient Summary: A group of Dutch specialists discussed the use of germline and tumour genetic testing in prostate cancer (PCa) patients, indication of these tests (which patients and when), and impact of these tests on the management and treatment of PCa., (© 2022 The Author(s).)

Background: The COVID-19 pandemic has disrupted regular health care with potential consequences for non-COVID diseases like cancer. To ensure continuity of oncological care, guidelines were temporarily adapted., Objective: To evaluate the impact of the COVID-19 outbreak on bladder cancer care in the Netherlands., Methods: The number of bladder cancer (BC) diagnoses per month during 2020-2021 was compared to 2018-2019 based on preliminary data from the Netherlands Cancer Registry (NCR). Additionally, detailed data were retrieved from the NCR for the cohort diagnosed between March 1 st -May 31 st 2020 (first COVID wave) and 2018-2019 (reference cohort). BC diagnoses, changes in age and stage at diagnosis, and time to first-line treatment were compared between both periods. Changes in treatment were evaluated using logistic regression., Results: During the first COVID wave (week 9-22), the number of BC diagnoses decreased by 14%, corresponding with approximately 300 diagnoses, but increased again in the second half of 2020. The decline was most pronounced from week 13 onwards in patients≥70 years and patients with non-muscle invasive BC. Patients with muscle-invasive disease were less likely to undergo a radical cystectomy (RC) in week 17-22 (OR = 0.62, 95% CI = 0.40-0.97). Shortly after the start of the outbreak, use of neoadjuvant chemotherapy decreased from 34% to 25% but this (non-significant) effect disappeared at the end of April. During the first wave, 5% more RCs were performed compared to previous years. Time from diagnosis to RC became 6 days shorter. Overall, a 7% reduction in RCs was observed in 2020., Conclusions: The number of BC diagnoses decreased steeply by 14% during the first COVID wave but increased again to pre-COVID levels by the end of 2020 (i.e. 600 diagnoses/month). Treatment-related changes remained limited and followed the adapted guidelines. Surgical volume was not compromised during the first wave. Altogether, the impact of the first COVID-19 outbreak on bladder cancer care in the Netherlands appears to be less pronounced than was reported for other solid tumors, both in the Netherlands and abroad. However, its impact on bladder cancer stage shift and long-term outcomes, as well as later pandemic waves remain so far unexamined., Competing Interests: Lambertus A. Kiemeney and J. Alfred Witjes are Editorial Board members of this journal, but were not involved in the peer-review process nor had access to any information regarding its peer-review. Lisa M.C. van Hoogstraten, Richard P. Meijer, Geert J.L.H. van Leenders, Ben G.L. Vanneste, Luca Incrocci, Tineke J. Smilde, Sabine Siesling, Katja K.H. Aben, the BlaZIB study group and the COVID and Cancer-NL consortium declare that they have no conflict of interest., (© 2022 – The authors. Published by IOS Press.)

Background: Radiolabeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has shown superior diagnostic accuracy to conventional imaging for the detection of prostate cancer deposits . Consequently, clinical management changes have been reported in patients with biochemical recurrence (BCR) of disease after robot-assisted radical prostatectomy (RARP). We hypothesized that, due to the exclusion of patients with metastatic disease on PSMA-PET/CT, those who underwent local salvage radiation therapy (SRT) after restaging PSMA-PET/CT for BCR may have better oncological outcomes than patients who underwent "blind" SRT., Objective: To compare the oncological outcome of a patient cohort that underwent PSMA-PET imaging prior to SRT with that of a patient cohort that did not have PSMA-PET imaging before SRT., Design, Setting, and Participants: We included 610 patients who underwent SRT, of whom 298 underwent PSMA-PET/CT prior to SRT and 312 did not. No additional hormonal therapy was prescribed., Outcome Measurements and Statistical Analysis: To compare both cohorts, case-control matching was performed, using the prostate-specific antigen (PSA) value at the initiation of SRT, pathological grade group, pathological T stage, surgical margin status, and biochemical persistence after RARP as matching variables. The outcome variable was biochemical progression at 1 yr after SRT, defined as either a rise of PSA ≥0.2 ng/ml above the nadir after SRT or the start of additional treatment., Results and Limitations: After case-control matching, 216 patients were matched in both cohorts (108 patients per cohort). In the patient cohort without PSMA-PET/CT prior to SRT, of 108 patients, 23 (21%) had biochemical progression of disease at 1 yr after SRT, compared with nine (8%) who underwent restaging PSMA-PET/CT prior to SRT (p = 0.007)., Conclusions: PSMA-PET/CT is found to be associated with an improved oncological outcome in patients who undergo SRT for BCR after RARP., Patient Summary: Performing prostate-specific membrane antigen positron emission tomography/computed tomography imaging in patients with biochemical recurrence of disease after robot-assisted radical prostatectomy, before initiating salvage radiation therapy, resulted in improved short-term oncological outcomes., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: The purpose of this review was to summarize the current literature on the assessment and treatment of radiation urethritis and cystitis (RUC) for the development of an evidenced-based management algorithm., Material and Methods: The PubMed/MEDLINE database was searched by a multidisciplinary group of experts in January 2021., Results: In total, 48 publications were identified. Three different types of RUC can be observed in clinical practice: inflammation-predominant, bleeding-predominant, and the combination of inflammation- and bleeding-RUC. There is no consensus on the optimal treatment of RUC. Inflammation-predominant RUC should be treated symptomatically based on the existence of bothersome storage or voiding lower urinary tract symptom as well as on pain. When bleeding-predominant RUC has occurred, hydration and hyperbaric oxygen therapy (HOT) should be used first and, if HOT is not available, oral drugs instead (sodium pentosane polysulfate, aminocaproic acid, immunokine WF 10, conjugated estrogene, or pentoxifylline + vitamin E). If local bleeding persists, focal therapy of bleeding vessels with a laser or electrocoagulation is indicated. In case of generalized bleeding, intravesical installation should be initiated (formalin, aluminium salts, and hyaluronic acid/chondroitin). Vessel embolization is a less invasive treatment with potentially less complications and good clinical outcomes. Open- or robot-assisted surgery is indicated in patients with permanent, life-threatening bleeding, or fistulae., Conclusions: Treatment of RUC, if not self-limiting, should be done according to the type of RUC and in a stepwise approach. Conservative/medical treatment (oral and topic agents) should primarily be used before invasive (transurethral) treatments., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Introduction: The COVID-19 outbreak has affected care for non-COVID diseases like cancer. We evaluated the impact of the COVID-19 outbreak on prostate cancer care in the Netherlands., Methods: Prostate cancer diagnoses per month in 2020-2021 versus 2018-2019 were compared based on preliminary data of the Netherlands Cancer Registry (NCR) and nationwide pathology network. Detailed data was retrieved from the NCR for the cohorts diagnosed from March-May 2020 (first COVID-19 wave) and March-May 2018-2019 (reference). Changes in number of diagnoses, age, disease stage and first-line treatment were compared., Results: An initial decline of 17% in prostate cancer diagnoses during the first COVID-19 wave was observed. From May onwards the number of diagnoses started to restore to approximately 95% of the expected number by the end of 2020. Stage at diagnosis remainedstable over time. In low-risk localised prostate cancer radical prostatectomy was conducted more often in week 9-12 (21% versus 12% in the reference period; OR=1.9, 95% CI; 1.2-3.1) and less active surveillance was applied (67% versus 78%; OR=0.6, 95% CI; 0.4-0.9). In the intermediate-risk group, a similar change was observed in week 13-16. Radical prostatectomy volumes in 2020 were comparable to 2018-2019., Conclusion: During the first COVID-19 wave the number of prostate cancer diagnoses declined. In the second half of 2020 this largely restored although the number remained lower than expected. Changes in treatment were temporary and compliant with adapted guidelines. Although delayed diagnoses could result in a less favourable stage distribution, possibly affecting survival, this seems not very likely., (Copyright © 2022. Published by Elsevier Ltd.)

Background and Purpose: 1.5 Tesla magnetic resonance imaging radiotherapy linear accelerator (MR-Linac) is gaining interest for treatment of localized prostate cancer. Clinical evidence is lacking and it therefore remains uncertain whether MR-Linac is cost-effective. An early health economic analysis was performed to calculate the necessary relative reduction in complications and the maximum price of MR-Linac (5 fractions) to be cost-effective compared to 5, 20 and 39 fractionation schedules of external beam radiotherapy (EBRT) and low-dose-rate (LDR) brachytherapy., Materials and Methods: A state transition model was developed for men with localized prostate cancer. Complication rates such as grade ≥2 urinary, grade ≥2 bowel and sexual complications, and utilities were based on systematic literature searches. Costs were estimated from a Dutch healthcare perspective. Threshold analyses were performed to identify the thresholds of complications and costs for MR-Linac to be cost-effective, while holding other outcomes such as biochemical progression and mortality constant. One-way sensitivity analyses were performed to outline uncertainty outcomes., Results: At €6460 per patient, no reductions in complications were needed to consider MR-Linac cost-effective compared to EBRT 20 and 39 fractions. Compared to EBRT 5 fractions and LDR brachytherapy, MR-Linac was found to be cost-effective when complications are relatively reduced by 54% and 66% respectively. Results are highly sensitive to the utilities of urinary, bowel and sexual complications and the probability of biochemical progression., Conclusions: MR-Linac is found to be cost-effective compared to 20 and 39 fractions EBRT at baseline. For MR-Linac to become cost-effective over 5 fractions EBRT and LDR brachytherapy, it has to reduce complications substantially or be offered at lower costs., Competing Interests: Declaration of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare no personal conflicts of interest. Several MR-Linac scientific projects at the Division of Imaging and Oncology of University Medical Center Utrecht have been partly funded Elekta AB (Stockholm, Sweden) and Philips Medical Systems (Best, The Netherlands)., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The purpose of this report was to systematically review the radiation enhancement factor (REF) effects of immunotherapy on radiotherapy (RT) to the local tumor in comparison with other traditional radiation sensitizers such as cisplatin. PubMed and Medline databases were searched until February 2019. Reports with abscopal effect in the results were excluded. Graphs of the selected papers were digitized using Plot Digitizer (Sourceforge.net) in order to calculate the tumor growth delay (TGD) caused by immunotherapy. To enable comparison between different studies,the TGD were used to define the REF between RT versus the RT/immunotherapy combination. Thirty-two preclinical papers, and nine clinical series were selected. Different mouse models were exposed to RT doses ranging from 1 to 10 fractions of 1.8 to 20 Gray (Gy) per fraction. Endpoints were heterogeneous, ranging from regression to complete local response. No randomized clinical studies were identified. The median preclinical REF effect of different immunotherapy was varying from 1.7 to 9.1. There was no relationship observed either with subclasses of immunotherapy orRT doses. In the clinical studies, RT doses ranged from 1 to 37 fractions of 1.8 to 24 Gy per fraction. Most clinical trials used ipilimumab and interleukin-2. Local control rate in the clinical series ranged from 66% to 100%. A strong REF of immunotherapy (1.7 to 9.1) was observed, this being higher than traditionally sensitizers such as cisplatin (1.1). This result implies that for the same RT dose, a higher local control was achieved with a combination of immunotherapy and RT in preclinical settings. This study therefore supports the use of combined RT and immunotherapy to improve local tumor control in clinical settings without exacerbation of toxicities., Competing Interests: All authors declare to have no conflict of interest., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era., Methods: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis., Results: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m 2 platinum dose administered (P trend  < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure., Conclusions: Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)